RESEARCH Open Access Micronutrient fortification of food and … · 2012. 11. 1. · approach is...

Das et al. Systematic Reviews 2013, 2:67http://www.systematicreviewsjournal.com/content/2/1/67

RESEARCH Open Access

Micronutrient fortification of food and its impacton woman and child health: a systematic reviewJai K Das, Rehana A Salam, Rohail Kumar and Zulfiqar A Bhutta*

Abstract

Background: Vitamins and minerals are essential for growth and metabolism. The World Health Organizationestimates that more than 2 billion people are deficient in key vitamins and minerals. Groups most vulnerable tothese micronutrient deficiencies are pregnant and lactating women and young children, given their increaseddemands. Food fortification is one of the strategies that has been used safely and effectively to prevent vitamin andmineral deficiencies.

Methods: A comprehensive search was done to identify all available evidence for the impact of fortificationinterventions. Studies were included if food was fortified with a single, dual or multiple micronutrients and impactof fortification was analyzed on the health outcomes and relevant biochemical indicators of women and children.We performed a meta-analysis of outcomes using Review Manager Software version 5.1.

Results: Our systematic review identified 201 studies that we reviewed for outcomes of relevance. Fortification forchildren showed significant impacts on increasing serum micronutrient concentrations. Hematologic markers alsoimproved, including hemoglobin concentrations, which showed a significant rise when food was fortified withvitamin A, iron and multiple micronutrients. Fortification with zinc had no significant adverse impact onhemoglobin levels. Multiple micronutrient fortification showed non-significant impacts on height for age, weight forage and weight for height Z-scores, although they showed positive trends. The results for fortification in womenshowed that calcium and vitamin D fortification had significant impacts in the post-menopausal age group. Ironfortification led to a significant increase in serum ferritin and hemoglobin levels in women of reproductive age andpregnant women. Folate fortification significantly reduced the incidence of congenital abnormalities like neuraltube defects without increasing the incidence of twinning. The number of studies pooled for zinc and multiplemicronutrients for women were few, though the evidence suggested benefit. There was a dearth of evidence forthe impact of fortification strategies on morbidity and mortality outcomes in women and children.

Conclusion: Fortification is potentially an effective strategy but evidence from the developing world is scarce.Programs need to assess the direct impact of fortification on morbidity and mortality.

Keywords: Child, Food, Fortification, Nutrition, Supplementation, Women

BackgroundVitamins and minerals are essential for growth and me-tabolism. The World Health Organization (WHO) esti-mates that more than 2 billion people are deficient inkey vitamins and minerals, particularly vitamin A, iod-ine, iron and zinc [1]. Most of these affected populationsare from developing countries where multiple micronu-trient (MMN) deficiencies coexist.

* Correspondence: [email protected] of Excellence in Women & Child Health, Aga Khan University, Karachi74800, Pakistan

© 2013 Das et al.; licensee BioMed Central LtdCommons Attribution License (http://creativecreproduction in any medium, provided the or

The population groups most vulnerable to these micro-nutrient deficiencies are pregnant and lactating womenand young children, given their increased demands [2,3].According to recent WHO estimates, globally about 190million preschool children and 19.1 million pregnantwomen are vitamin A deficient (that is, have serum retinol

Das et al. Systematic Reviews 2013, 2:67 Page 2 of 24http://www.systematicreviewsjournal.com/content/2/1/67

1.62 billion people are anemic, with the highest prevalenceamong preschool children (47%) followed by pregnantwomen (42%) [7]. Suboptimal vitamin B6 and B12 statushave also been observed in many developing countries [8].These micronutrient deficiencies are also associated withincreased incidence and severity of infectious illness andmortality from diarrhea, measles, malaria and pneumonia[9]. The consequences of micronutrient deficiencies arenot limited to health parameters alone but have far-reaching effects on economies through secondary physicaland mental disabilities and altered work productivity.Several strategies have been employed to supplement

micronutrients to women and children [10-13]. Theseinclude education, dietary modification, food rationing,supplementation and fortification. Food fortification isone of the strategies that has been used safely and effect-ively to prevent micronutrient deficiencies and has beenpracticed in developed countries for well over a centurynow. In the early 20th century, salt iodization began inSwitzerland; vitamin A-fortified margarine was intro-duced in Denmark in 1918; and in the 1930s, vitaminA-fortified milk and iron and B complex flour was in-troduced in a number of developed countries. Thesefortification strategies are now almost universal in thedeveloped world and increasingly deployed in manymiddle-income countries. Relatively few of these pro-grams have been adequately evaluated to assess their im-pact on population health [14].WHO categorizes food fortification strategies into

three possible approaches: mass, targeted, and marketdriven [14]. Mass fortification involves foods that arewidely consumed, such as wheat, salt, sugar; targeted ap-proaches fortify foods consumed by specific age groupslike infant complementary foods; and the market-drivenapproach is when a food manufacturer fortifies a specificbrand for a particular consumer niche. Food vehiclescommonly used can be grouped into three broad cat-egories: staples (wheat, rice, oils), condiments (salt, soysauce, sugar), and processed commercial foods (noodles,infant complementary foods, dairy products).Food fortification is an attractive public health strategy

and has the advantage of reaching wider at-risk populationgroups through existing food delivery systems, without re-quiring major changes in existing consumption patterns[13,15]. Compared with other interventions, food fortifica-tion may be cost-effective and, if fortified foods are regu-larly consumed, has the advantage of maintaining steadybody stores [15].There are a number of systemic reviews and meta-

analyses analyzing the effect of food fortification onhealth outcomes. An extensive review of zinc forti-fication in children described an overall significantimpact on serum zinc levels with no adverse effects[16]. Reviews on MMN fortification in children showed

improved micronutrient status and reduced anemiaprevalence [10,17]. A review of iron fortification in thegeneral population also showed an increase in serumhemoglobin levels and decreased anemia prevalence[18]. Although iron, zinc and MMN fortification hasbeen consistently analyzed, literature on vitamin A, iod-ine and vitamin D fortification in children has not beensufficiently assessed. Furthermore, iron and MMN forti-fication in women of different age groups has not beenadequately evaluated. We therefore feel that the currentevidence of certain micronutrients and population groupsmay not be sufficient for providing a way forward.Hence we undertook a systematic review of the currentevidence to assess the effectiveness of food fortificationwith single micronutrients (iron, folic acid, vitamin A,vitamin D, iodine, zinc) as well as MMN when com-pared with no fortification on the health and nutritionof women and children.

Conceptual frameworkWe analyzed the impact of micronutrient fortificationstrategies - single, dual or multiple - on various out-comes guided by our conceptual framework (Figure 1).These micronutrients were administered through one ofthe three food vehicles (staples, condiments or processedfoods) to reach the population targeted. For the scope ofthis review, we focused on a priori defined populationgroups of infants, children and adolescents under 18years of age, WRA and post-menopausal women. Theoutcomes analyzed were broadly categorized into bio-chemical indicators, hematologic markers, anthropometricindicators, pregnancy outcomes, and relevant morbidityand mortality.

MethodsSearch strategyAll available evidence for the impact of fortification in-terventions was systematically retrieved and analyzed.A comprehensive search was done for key words in-cluding Medical Subject Headings and free text termsfor all the micronutrients included in this review. Wesearched MEDLINE, PubMed, POPLINE, Literatura LatinoAmericana em Ciências da Saúde, Cumulative Index toNursing and Allied Health Literature, Cochrane Library,British Library for Development Studies at the Inter-national Development Statistics, WHO regional databasesand the IDEAS database of unpublished working papers,Google and Google Scholar. Detailed manual searcheswere undertaken, including cross-references and bibliog-raphies of available data and publications. Existing relevantreviews were used to identify additional sources of infor-mation. The search was extended to review the gray litera-ture in non-indexed and non-electronic sources. The

IRON

FOLIC ACID

ZINC

VITAMIN A

IODINE

VITAMIN DCALCIUM

MULTIPLE MICRONUTRIENTS

STAPLES

CONDIMENT

PROCESSED FOODS

INFANT

CHILDREN

WOMEN OF REPRODUCTIVE

AGE

POST MENOPAUSAL

WOMEN

BIO-CHEMICAL INDICATORS

ANTHROPOMETRIC INDICATORS

HEMATOLOGIC MARKERS

MORTALITY

MORBIDITY

PREGNANCY OUTCOMES

Figure 1 Conceptual framework.


bibliographies of books with relevant sections were alsosearched manually to identify relevant reports and publica-tions. We did not apply any language or date restrictionand the date of last search was 1 November 2012.

Inclusion and exclusion criteriaWe included randomized controlled trials (RCTs), quasi-experimental and before-after studies. In addition, otherless rigorous study designs like observational studies (co-hort and case–control), program evaluations and de-scriptive studies were also reviewed to understand thecontext in which these interventions were implemented.Studies were included if food was fortified with a single,dual or multiple micronutrients and the impact of forti-fication was analyzed on the health outcomes and rele-vant biochemical indicators of women and children. Weincluded studies with children and adolescents of all agegroups - infants and preschool children (ages 2 to 5years), school-going children (ages of above 5 years) andadolescents till 18 years of age. For women, we includedstudies on pre-pregnant women, WRA, and post-menopausal women. The control groups in the includedtrials either received unfortified foods or regular diets.Studies were included if they measured the relevant out-comes according to our conceptual framework describedabove and if the data for these outcomes were presentedin a manner that could be included in the meta-analysis.Studies were not considered that focused on home for-tification with micronutrient powders, food contents,intake levels, bioavailability, comparisons between diffe-rent food vehicles or comparisons among compounds of

the same micronutrient, comparisons between fortifica-tion and supplementation, bio-fortification and studiesevaluating the sensory impacts of fortification.

Study selection processAll the available studies underwent triage with standard-ized criteria for evaluating outputs from primary screening.Following an agreement on the search strategy, the ab-stracts and full texts were screened by two independent ab-stractors to identify studies adhering to the objectives. Anydisagreements on selection of studies between the two pri-mary abstractors were resolved by the third reviewer.

Data extractionAfter retrieval of the full texts of all the relevant studies,each study was double data abstracted into a standard-ized form, which included the following details.

General informationTitle, author, year of publication, country of intervention,study design.

InterventionStudy duration, characteristics of intervention and com-parison groups.

FortificationMicronutrient fortified, food vehicle used, fortificantcompound and its concentration in the food.


Key outcome measuresOutcome measures were identified and evaluated separ-ately for the various micronutrients. Relevant biochem-ical indicators included serum micronutrient levels andhematologic markers (anemia, iron deficiency anemia,hemoglobin). Anthropometric indicators were stunting;wasting; underweight; and changes in Z-scores for heightfor age (HAZ), weight for age (WAZ) and weight forheight (WHZ). Pregnancy outcomes included twinningand congenital abnormalities. Morbidity outcomes in-cluded diarrhea, pneumonia, malaria, urinary tract infec-tions (UTI), fever and mortality (Table 1). These werereported as means, standard deviations, number ofevents or other usable outcomes that could be pooled.Where information was missing or incomplete, the au-thors were contacted for clarification and access to data.In cases where it was not possible, the outcome was notconsidered for further analysis.

Data analysisWe performed meta-analyses of all outcomes usingReview Manager Software version 5.1. For dichotomousdata, we presented results as summary risk ratio (RR)and odds ratio (OR) and their respective 95% confidenceintervals (CI). For continuous data, we used the standardmean difference (SMD) if outcomes were comparable.We performed separate meta-analyses for RCTs or quasiexperimental and before-after studies to maintain thequality of evidence. Results of before-after meta-analyseswere only reported if there were no RCTs or quasi-experimental studies in a particular category of micronu-trient fortification. For analyzing and pooling clusterrandomized trial data, the entire cluster was used as theunit of randomization and the analysis was adjusted fordesign. The data of cluster-randomized trials were incor-porated using a generic inverse variance method inwhich logarithms of RR estimates were used along withthe standard error of the logarithms of RR estimates.Subgroup analyses were performed according to the dif-ferent age groups, countries, population characteristics,type of food fortified and the duration of intervention.

Table 1 Outcomes for various micronutrients analyzed

Micronutrient Outcomes analyzed

Zinc Serum zinc concentration, height velocity, alkaline ph

Folate Serum folate concentration, red blood cell folate conanencephaly and spina bifida

Vitamin A Serum vitamin A concentration, vitamin A deficiency

Vitamin D/calcium Serum 25-hydroxy vitamin D3 concentration, alkaline

Iodine Serum thyroxin levels, prevalence of hypothyroidism

Iron Serum ferritin, serum transferrin, hemoglobin and ane

Multiplemicronutrients

Serum ferritin, serum zinc, serum retinol, vitamin A deZ-scores, weight for age Z-scores, weight for height Z

For the outcomes where only medians were reported,medians were converted to approximate of the meansand then pooled for analysis [19].The level of attrition was noted for each study and its

impact on the overall assessment of treatment effect ex-plored by using sensitivity analysis. Heterogeneity betweentrials was assessed using the I-squared statistic (I2 >30)and a p-value

Table 2 Definitions of various micronutrient deficiencies

Term Definition

Anemiaa Children 6 to 59 months of age: Hb less than 110g/l

Children 5 to 11 years of age: Hb less than 115 g/l

Children 12 to 14 years of age: Hb less than 120g/l

Women 15 years and older: Hb less than 120 g/l

Vitamin Adeficiencyb

Plasma (serum) retinol concentration of less than20 μg/dl

Zinc deficiencyc Serum zinc concentration of less than 10.7 μmol/L

Asymptomatic zincdeficiency

Serum zinc concentration of less than 10.7 μmol/L with the absence of clinical signs andsymptoms.

a Adapted from WHO VIMNIS (available from http://www.who.int/vmnis/indicators/haemoglobin/en/) [229].b Adapted from WHO. Global prevalence of vitamin A deficiency inpopulations at risk 1995–2005 [230].c Adapted from WHO. Trace elements in human nutrition and health. Geneva,Switzerland: WHO, 1996 [231] Hb, hemoglobin.

Figure 2 Summary of search strategy.


children and 79 [146-224] were on women, while one studyhad both women and children as their study population [33](Figure 2). Furthermore 125 [25-28,30,32-39,41-44,47,48,51,53,54,56,59,60,62,63,65-73,75-77,81-83,85,86,88-90,92,93,95-104,107-109,111-117,119-127,129,130,132-136,139-144,223,225-228] of these trials were RCTs; the rest werequasi-experimental [46,55,61,74,78,87,91] and before-after studies [29,31,40,45,49,50,52,57,58,79,80,84,94,95,105,131,137,138,149,150,153,157,159-169,172,174,177,181,183-186,189-191,193,195-200,202,205-211,213,219-222,224].Various micronutrients were used as fortificants in thesestudies including iron, zinc, vitamin A, folate, iodine, cal-cium and vitamin D alone and in combination. Food vehi-cles chosen varied for each micronutrient fortification andare described in detail in the relevant section. For the 125RCTs included in this review, randomization and allocationconcealment were adequate in 41 of the studies[33-37,56,60,63,65,68,69,72,75,77,83,88,92,97,99,101,103,107,108,112,113,115,116,122,125,127,132,135,139,140,142,143,146,147,188,214,217], information regarding attrition rateswas adequately discussed with reasons in 110 studies[33-39,41-44,47,48,51,53,54,56,59,60,62,63,65,67-73,75-77,81-83,85,86,88-90,92,93,96-104,107-109,111-117,119-127,129,130,132-136,139-144,171,173,175,176,178-180,182,187,188,192,194,201,212,214-218,223] and blinding was de-scribed adequately in 62 studies [25,26,28,30,32,35,38,39,47,48,51,53,54,56,59,60,62,65,67-72,75-77,81,83,86,93,96,99,

100,103,108,109,113,116,119,123-125,130,133,134,140-144,146,170,171,179,180,182,187,192,194,201]. The studies pro-vided insufficient information on selective reporting, whichlimited us from making any judgment. We analyzed theoutcomes separately for women and children and the out-comes analyzed for each micronutrient fortification are

http://www.who.int/vmnis/indicators/haemoglobin/en/http://www.who.int/vmnis/indicators/haemoglobin/en/

Table 3 Summary of results for iron fortification in children

Outcome/quality ofevidence

Combinedeffect

Population Age groups Country Fortificant type Food vehicle

General/healthypopulation(studies/participants)

Deficientpopulation

Infants Preschooland school-goingchildren

Low- andlower middleincomecountries

Upper middle-and higher-incomecountries

Ferroussulfate

NaFeEDTA Processedfood

Staples Condiments

Hemoglobinlevels

SMD: 0.55(95% CI:0.34, 0.76)

SMD: 0.50 (95%CI: 0.28, 0.71)

SMD: 0.79(95% CI:0.19, 1.38)

SMD: 0.81(95% CI:0.31, 1.31)

SMD: 0.46(95% CI: 0.24,0.67)

SMD: 0.32(95% CI: 0.14,0.50)

SMD: 0.67 (95%CI: 0.36, 0.97)

SMD: 0.50(95% CI:0.14, 0.86)

SMD: 0.76(95% CI:0.06, 1.47)

SMD: 0.55(95% CI:0.29, 0.82)

SMD: 0.44(95% CI:0.10, 0.79)

SMD: 1.14(95% CI: -0.09, 2.37)

Quality ofevidence:Moderate

25 studies 5,083participants

6 studies1,184participants









3 studies705participants

Serumferritinlevels

SMD: 0.91(95% CI:0.38, 1.44)

SMD: 0.63 (95%CI: 0.28, 0.98)

SMD: 1.37(95% CI:0.01, 2.74)

SMD: 0.63(95% CI:0.28, 0.98)

SMD: 1.37(95% CI: 0.01,2.74)

SMD: 1.37(95% CI: 0.01,2.74)

SMD: 0.68 (95%CI: 0.49, 0.87)

SMD: 0.84(95% CI:0.60, 1.09)

SMD: 1.83(95% CI: -0.08, 3.73)

SMD: 0.66(95% CI:0.36, 0.97)

SMD: 0.48(95% CI:0.17, 0.78)

SMD: 2.80(95% CI:2.43, 3.17)


4 studies 952participants









1 study 170participants


Effect onanemia

RR: 0.55(95% CI:0.42, 0.72)

RR: 0.64 (95% CI:0.50, 0.82)

RR: 0.23(95% CI:0.04, 1.25)

RR: 0.42(95% CI:0.24, 0.72)

RR: 0.60(95% CI: 0.43,0.84)

RR: 0.91 (95%CI: 0.72, 1.14)

RR: 0.41 (95%CI: 0.28, 0.61)

RR: 0.52(95% CI:0.34, 0.79)

RR: 0.46(95% CI:0.17, 1.23)

RR: 0.46(95% CI:0.28, 0.76)

RR: 0.81(95% CI:0.60, 1.10)

RR: 0.12(95% CI:0.01, 2.16)













Estimates in bold show significant impacts. CI, confidence interval; NaFeEDTA, sodium iron ethylenediaminetetraacetate RR: relative risk; SMD: standard mean difference.

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Table 4 Summary of results for zinc fortification in children


Combinedeffect

Age groups Zinc compound used forfortification

Food vehicle Duration

Newbornswith verylow birthweight

Fullterm

healthyinfants

Infantsat risk ofstunting

Malnourishedinfants

School-goingchildren

School-goingchildren withasymptomaticzinc deficiency

Zincsulfate

Zincchloride

Zincacetate

Milkproducts

Cerealproducts

Less than6 months

6 monthsor more

Serum zinclevels

SMD: 1.28(95% CI:0.56, 2.01)

SMD: 0.51(95% CI: -0.32, 1.34)

SMD:3.49

(95% CI:-0.36,7.33)

SMD: 0.09(95% CI: -0.24, 0.41)

SMD: 0.12 (95%CI: -0.55, 0.78)

SMD: 1.12(95% CI: -0.21, 2.46)

SMD: 2.77(95% CI: 1.43,

4.11)

Nostudiesidentified

Nostudiesidentified

Nostudiesidentified

SMD: 1.46(95% CI:0.26, 2.66)

SMD: 1.16(95% CI:0.08, 2.24)

SMD: 1.48(95% CI:0.57, 2.39)

SMD: 1.51(95% CI:0.13, 2.89)


2 studies64

participants

2 studies71

infants

1 study147

infants

1 study 35infants

2 studies347

participants

1 study 19children

5 studies176

participants

4 studies513

participants

4 studies381

participants

4 studies155

participants

Hemoglobinlevel

SMD: -0.11(95% CI: -0.52, 0.31)

No studiesidentified

Nostudiesidentified

Nostudiesidentified

f




SMD:0.00

(95% CI:-0.67,0.67)

SMD: -0.39 (95%CI: -1.03,0.24)

SMD:0.28

(95% CI:-0.62,1.19)

SMD: -0.21(95% CI: -0.67, 0.25)

SMD: 0.28(95% CI: -0.62, 1.19)



Quality ofevidence:Low

1 study34

children

1 study39

children

1 study19

children

2 studies73

participants


Serumcopper levels

SMD: 0.57(95% CI: -0.91, 2.06)


SMD:0.75

(95% CI:-1.65,3.16)

Nostudiesidentified

SMD: 0.21 (95%CI: -0.46, 0.87)



Nostudiesidentified

Nostudiesidentified

Nostudiesidentified

SMD: 0.57(95% CI: -0.91, 2.06)

SMD: -0.61(95% CI: -1.54, 0.31)



Quality ofevidence:Very low

3 studies126

infants

1 study 35infants

3 studies142

participants


Serumalkalinephosphataselevels

SMD: 0.94(95% CI: -0.29, 2.17)


SMD:0.68

(95% CI:-0.90,2.25)

Nostudiesidentified



SMD: 1.56(95% CI: 0.50,

2.62)

Nostudiesidentified

Nostudiesidentified

Nostudiesidentified

SMD: 0.68(95% CI: -0.90, 2.25)

SMD: 1.56(95% CI:0.50, 2.62)




2 studies100

infants

1 study 19children

2 studies100

participants


Weight gain SMD: 0.50(95% CI: -0.12, 1.11)

SMD: 0.33(95% CI: -0.33, 0.99)

SMD:1.48

(95% CI:-1.49,4.45)

SMD: 0.00(95% CI: -0.30, 0.30)

SMD: -0.10(95% CI: -0.73,

0.52)

SMD: 0.25(95% CI: -0.17, 0.67)


Nostudiesidentified

Nostudiesidentified

Nostudiesidentified

SMD: 0.77(95% CI: -0.43, 1.96)

SMD: 0.08(95% CI:-0.16, 0.33)



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Table 4 Summary of results for zinc fortification in children (Continued)


1 study 36infants

2 studies80

infants

1 study176

infants

1 study 39infants

1 study 88children

4 studies155

participants

2 studies264

participants

Heightgrowth

SMD: 0.52(95% CI:0.01, 1.04)

SMD: 0.70(95% CI:0.02, 1.37)

SMD: -0.48 (95%CI: -2.45,1.48)

SMD: 0.05(95% CI: -0.25, 0.35)

SMD: 0.16 (95%CI: -0.47, 0.79)

SMD: 0.31(95% CI: -0.11, 0.74)


Nostudiesidentified

Nostudiesidentified

Nostudiesidentified

SMD: -0.09(95% CI: -1.17, 0.99)

SMD: 0.14(95% CI: -0.11, 0.38)




1 study 36infants

2 studies80

infants

1 study176

infants

1 study 39infants

1 study 88children

5 studies187

participants

2 studies264

participants

CI, confidence interval; SMD: Standard mean difference. Estimates in bold show significant impacts.

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Table 5 Summary of results for iodine, Vitamin A and calcium/vitamin D fortification in children

Iodine fortification


Combined effect

Serum thyroxin levels SMD: 0.45 (95% CI: -1.15,2.06)

2 studies 1,131 participants reported this outcome. The studies were conducted inAfrica on school-going children.

Quality of evidence: Low

Urinary iodineconcentrations

SMD: 6.39 (95% CI: 2.69,10.08)

2 studies 1,016 participants reported this outcome. The studies were conducted inAfrica on school-going children.

Quality of evidence:Moderate

Vitamin A fortification


Combined effect

Hemoglobin levels SMD: 0.48 (95% CI: 0.07,0.89)

2 studies with1,538 participants reported the outcome. The study by Zhang et al. [132]used four different comparison groups. The first group received low amounts ofvitamin A-fortified biscuits for 9 months daily. The second group received highamount of vitamin A-fortified biscuits for 3 months daily. The third group receivedvery high amounts of vitamin A-fortified biscuits for 3 months weekly. The standardmean differences for the three groups were 0.73 (95% CI: 0.42, 1.04), 0.62 (95% CI: 0.38,0.85) and 0.63 (95% CI: 0.38, 0.88) respectively.

Quality of evidence: Low

Serum vitamin Aconcentration

SMD: 0.61 (95% CI: 0.39,0.83)

3 studies with 2,362 participants reported the outcome. The study by Zhang et al.[132] used four different comparison groups as explained in comments forhemoglobin levels. The standard mean differences for the three groups were 0.52(95% CI: 0.21, 0.82), 0.73 (95% CI: 0.49, 0.97) and 0.44 (95% CI: 0.22, 0.66).Quality of evidence: Low

Vitamin A deficiency RR: 0.39 (95% CI: 0.09, 1.74) 2 studies with 1,465 participants reported the outcome. The study by Zhang et al.[132] showed positive impacts in reducing vitamin A deficiency whereas the study bySolon et al. [110] showed negative impacts. The latter used monosodium glutamatefor vitamin A fortification and the quantity of vitamin A used was much less than thatused by Zhang et al.


Calcium and vitamin D fortification


Combined effect Calcium only Vitamin D only Calcium and vitamin D

Serum parathyroid hormonelevels

SMD: -0.40 (95% CI: -0.56,-0.24)

SMD: -0.28 (95% CI: -0.50,-0.06)

No studies identified SMD: -0.52 (95% CI: -0.74,-0.29)

Quality of evidence: Low 2 studies 317 participants 2 studies 327 participants

Serum vitamin D levels SMD: 1.23 (95% CI: 0.35,2.11)

SMD: -0.15 (95% CI: -0.41,0.10)

SMD: 1.76 (95% CI: 0.37,3.15)

SMD: 1.58 (95% CI: 1.28,1.87)


1 study 233 participants 2 studies 651 participants 1 study 235 participants

Serum calcium levels SMD: -0.40 (95% CI: -0.59,-0.20)

SMD: -0.30 (95% CI: -0.56,-0.04)

No studies identified SMD: -0.50 (95% CI: -0.76,-0.24)

Quality of evidence: Low 1 study 231 participants 1 study 235 participants

Estimates in bold show significant impacts. CI, confidence intervals; RR: relative risk; SMD: standard mean difference.


outlined in Table 1. Definitions of various outcomes usedare outlined in Table 2. The characteristics of the includedstudies and quality assessment of the evidence are summa-rized below and in Tables 3, 4, 5, 6, 7 and 8 and further de-tails along with the forest plots are provided in Additionalfiles 1, 2 and 3.

ChildrenIron fortificationA total of 41 [25,26,28,30-32,35,39,48,49,54,56,57,65,70,77,80,81,83,85,88,89,97,99,101,104,106-108,112,113,114,116,

120,124,126,127,129,135,136,139] studies reported out-comes for impact of iron fortification. Four of the studieswere before-after studies and the rest were RCTs. Nineteenof these studies had infants as their study population, forti-fying formula milk, cow’s milk and complementary babyfoods. Condiments such as curry powder, fish sauce andsoy sauce were the vehicles used in a few studies targetingAsian populations. Drinking water, food bars, candies, noo-dles and fruit juices were also assessed as potential vehiclesby various studies. Seven studies used sodium iron ethyl-enediaminetetraacetate (NaFeEDTA) and 15 used ferrous

Table 6 Summary of results for multiple micronutrient fortification in children


Combinedeffect

Age groups Country Number of micronutrients used Duration of fortification

General/healthy

population

Deficientpopulation

Infants Preschooland school-

goingchildren

Low- andlower middle-

incomecountries

Upper middle-and higher-incomecountries

5 or less 6 to 12 More than12

Less than6 months

6 to 11months

12months or

more

Hemoglobinlevels

SMD: 0.75(95% CI:0.41, 1.08)

SMD: 0.72(95% CI:0.37, 1.07)

SMD: 1.06(95% CI:0.75, 1.38)

SMD: 1.05(95% CI:0.48, 1.63)

SMD: 0.45(95% CI:0.12, 0.79)

SMD: 0.50(95% CI: 0.21,

0.78)

SMD: 1.25(95% CI: 0.45,

2.06)

SMD: 1.50(95% CI: -0.23, 3.23)

SMD: 0.51(95% CI:0.24, 0.78)

SMD: 0.71(95% CI:0.32, 1.09)

SMD: 0.07(95% CI: -0.17, 0.31)

SMD: 1.05(95% CI:0.55, 1.56)

SMD: 0.52(95% CI:0.07, 0.98)


13 studies2,876

participants


7 studies1,508

participants

7 studies1,543

participants



4 studies747

participants

6 studies1,449

participants

4 studies855

participants

2 studies310

participants

8 studies2,025

participants

4 studies716

participants

Serumferritinlevels

SMD: 0.37[0.13, 0.62)

SMD: 0.37(95% CI:0.13, 0.62)


SMD: 0.43(95% CI:0.17, 0.68)

SMD: 0.06(95% CI: -0.17,

0.29)

SMD: 0.47(95% CI: 0.14,

0.80)

SMD: 0.18 (95%CI: -0.03, 0.40)

SMD: 0.45(95% CI:0.00, 0.90)

SMD: 0.62(95% CI:0.18, 1.06)

SMD: 0.17(95% CI: -0.16, 0.50)

SMD: 0.45(95% CI:0.00, 0.90)

SMD: 0.48(95% CI:0.07, 0.89)

SMD: 0.20(95% CI: -0.23, 0.64)


7 studies1,848

participants

6 studies1,547

participants





2 studies748

participants

4 studies1,021

participants


3 studies1,049

participants

3 studies7,20

participants

Serum zinclevels

SMD: 0.08[−0.02,0.19)

SMD: 0.08(95% CI: -0.02, 0.19)


SMD: 0.04(95% CI: -0.10, 0.17)

SMD: 0.17(95% CI:0.04, 0.30)

SMD: 0.12(95% CI: 0.01,

0.23)

SMD: -0.02 (95%CI: -0.26, 0.23)

SMD: -0.12(95% CI: -0.75, 0.51)

SMD: 0.13(95% CI: -0.02, 0.29)

SMD: 0.06(95% CI: -0.05, 0.17)

SMD: 0.31(95% CI:0.06, 0.57)

SMD: 0.06(95% CI: -0.09, 0.21)

SMD: 0.02(95% CI: -0.11, 0.15)


11 studies2,972

participants

7 studies1,780

participants

4 studies1,192

participants



2 studies232

participants

4 studies1,820

participants

5 studies920

participants

1 study223

children

6 studies1,128

participants

4 studies1,221

participants

Serumretinol levels

SMD: -0.05[−0.23,0.13)

SMD: 0.05(95% CI: -0.23, 0.13)


SMD: 0.04(95% CI: -0.22, 0.30)

SMD: -0.21(95% CI: -0.34,

-0.07)

SMD: -0.06(95% CI: -0.25,

0.14)

SMD: 0.01 (95%CI: -0.63, 0.64)

SMD: -0.28(95% CI: -0.45, -0.11)

SMD: -0.03(95% CI: -0.33, 0.27)

SMD: 0.02(95% CI: -0.27, 0.31)


SMD: -0.08(95% CI: -0.29, 0.13)

SMD: 0.03(95% CI: -0.37, 0.43)


8 studies1,927

participants

4 studies964

participants



to 2 studies 607participants

2 studies533

participants

5 studies878

participants

3 studies516

participants

3 studies1,676

participants

3 studies251

participants

Effect onanemia

RR: 0.55(95% CI:0.42, 0.71)

RR: 0.59(95% CI:0.46, 0.75)

RR: 0.20(95% CI:0.10, 0.40)

RR: 0.59(95% CI:0.50, 0.70)

RR: 0.45(95% CI:0.22, 0.89)

RR: 0.50 (95%CI: 0.37, 0.67)

RR: 0.69 (95% CI:0.41, 1.15)




RR: 0.77(95% CI:0.43, 1.36)

RR: 0.54(95% CI:0.36, 0.83)

RR: 0.50(95% CI:0.33, 0.77)


9 studies2,880

participants


5 studies1809

participants

5 studies1246

participants



1 study223

children

4 studies1,097

participants

5 studies1,726

participants

Effect onvitamin Adeficiency

RR: 0.90(95% CI:0.76, 1.06)

RR: 0.90(95% CI:0.76, 1.06)


RR: 0.85(95% CI:0.69, 1.03)

RR: 1.02 (95%CI: 0.76, 1.38)

RR: 0.88 (95%CI: 0.73, 1.07)

RR: 0.95 (95% CI:0.66, 1.36)





RR: 0.85(95% CI:0.71, 1.03)

RR: 1.14(95% CI:0.76, 1.71)


6 studies2,036

participants

3 studies687

participants

3 studies1349

participants



3 studies1,308

participants

3 studies728

participants

Height-for-age Z-score

SMD: 0.13(95% CI: -0.04, 0.29)

SMD: 0.12(95% CI: -0.09, 0.32)

SMD: 0.22(95% CI: -0.04, 0.47)

SMD: 0.26(95% CI:0.12, 0.40)

SMD: -0.01(95% CI: -0.21,

0.20)

SMD: 0.09 (95%CI: -0.17, 0.34)

SMD: 0.18(95% CI: 0.02,

0.34)

SMD: -0.00(95% CI: -0.19, 0.18)

SMD: 0.11(95% CI: -0.12, 0.34)

SMD: 0.18(95% CI: -0.07, 0.42)

SMD: 0.01(95% CI: -0.13, 0.15)

SMD: 0.11(95% CI: -0.12, 0.34)

SMD: 0.39(95% CI:0.24, 0.55)

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Table 6 Summary of results for multiple micronutrient fortification in children (Continued)


6 studies1,853

participants

2 studies245

participants

5 studies1,083

participants

3 studies1,009

participants



2 studies624

participants

1 study288

participants

5 studies1,180

participants

5 studies1,170

participants

1 study288

participants

2 studies634

participants

Weight-for-age Z-score

SMD: -0.12(95% CI: -0.43, 0.20)

SMD: 0.05(95% CI: -0.09, 0.18)

SMD: 0.18(95% CI: -0.14, 0.49)

SMD: -0.28(95% CI: -0.85, 0.29)

SMD: 0.09(95% CI: -0.16,

0.33)

SMD: 0.10 (95%CI: -0.13, 0.32)

SMD: -0.48 (95%CI: -1.45, 0.49)

SMD: -0.02(95% CI: -0.28, 0.24)

SMD: -0.03(95% CI: -0.26, 0.20)

SMD: -0.22(95% CI: -0.76, 0.33)

SMD: -0.25(95% CI: -0.90, 0.41)

SMD: 0.06(95% CI: -0.09, 0.21)

SMD: -0.68(95% CI: -2.79, 1.42)


6 studies1,853

participants

2 studies245

participants

5 studies1083

participants

3 studies1,009

participants



2 studies624

participants

1 study288

participants

5 studies1,180

participants

5 studies1,170

participants

1 study288

participants

2 studies634

participants

Weight-for-height Z-score

SMD: -0.11(95% CI: -0.40, 0.17)

SMD: -0.17(95% CI: -0.56, 0.22)

SMD: -0.56(95% CI: -1.42, 0.31)

SMD: 0.08(95% CI: -0.06, 0.21)

SMD: -0.39(95% CI: -1.06,

0.28)

SMD: 0.07 (95%CI: -0.07, 0.20)

SMD: -0.40 (95%CI: -1.17, 0.38)

SMD: -0.01(95% CI: -0.29, 0.26)

SMD: -0.14(95% CI: -0.37, 0.09)

SMD: -0.16(95% CI: -0.66, 0.34)

SMD: -0.10(95% CI: -0.75, 0.56)

SMD: -0.23(95% CI: -0.64, 0.18)

SMD: 0.18(95% CI:0.02, 0.34)


6 studies1,853

participants

2 studies245

participants

5 studies1,083

participants

3 studies1,009

participants



2 studies624

participants

1 study288

participants

5 studies1,180

participants

5 studies1,170

participants

1 study288

participants

2 studies634

participants

Estimates in BOLD show significant impacts. CI, confidence intervals; RR: relative risk; SMD: standard mean difference.

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Table 7 Summary of results for iron, folate and calcium/vitamin D fortification in women

Iron fortification


Combinedeffect

Population Country Fortificant type Food vehicle

General/healthy

population

Deficientpopulation

Low- and lowermiddle-income

countries

Upper middle- andhigher-income

countries

Ferroussulfate

NaFeEDTA Processedfood

Staples Condiments

Hemoglobinlevels

SMD: 0.62(95% CI: 0.36,0.89)

SMD: 0.66(95% CI: 0.30,

1.02)

SMD: 0.59(95% CI: 0.34,

0.83)

SMD: 0.52 (95% CI: -0.12, 1.16)

SMD: 0.66 (95% CI:0.31, 1.00)

SMD: 0.44(95% CI: 0.21,

0.67)

SMD: 0.48(95% CI: 0.22,

0.73)

SMD: 0.50(95% CI: 0.30,

0.70)

SMD: 0.90(95% CI: -0.10,

1.90)

SMD: 0.45(95% CI: 0.22,

0.68)









3 studies1,211

participants


Serum ferritinlevels

SMD: 0.41(95% CI: 0.23,0.60)

SMD: 0.23(95% CI: 0.08,

0.38)

SMD: 0.75(95% CI: 0.47,

1.03)

SMD: 0.48 (95% CI:0.31, 0.66)

SMD: 0.39 (95% CI:0.17, 0.61)

SMD: 0.42(95% CI: 0.05,

0.78)

SMD: 0.45(95% CI: 0.21,

0.69)

SMD: 0.46(95% CI: 0.10,

0.82)

SMD: 0.17(95% CI: -0.15,

0.49)

SMD: 0.50(95% CI: 0.33,

0.68)

Quality ofevidence: Low








to 2 studies993

participants


Effect onanemia

RR: 0.68 (95%CI: 0.49, 0.93)

RR: 0.65 (95%CI: 0.40, 1.04)

RR: 0.74 (95%CI: 0.61, 0.90)

RR: 0.74 (95% CI:0.61, 0.90)

RR: 0.67 (95% CI: 0.39,1.17)

RR: 0.57 (95%CI: 0.34, 0.94)

RR: 0.74 (95%CI: 0.61, 0.90)

RR: 0.51 (95%CI: 0.21, 1.25)

RR: 0.67 (95%CI: 0.39, 1.17)

RR: 0.74 (95%CI: 0.61, 0.90)









2 studies1,056

participants


Folate fortification


Combinedeffect

Quantity Duration

40 μg/100 g More than 100 μg/100 g Less than 1 year Greater than 1 year

Neural tubedefects

RR: 0.57 (95%CI: 0.45, 0.73)

RR: 0.80 (95% CI: 0.75, 0.86) RR: 0.55 (95% CI: 0.41, 0.75) RR: 0.52 (95% CI: 0.28, 0.97) RR: 0.60 (95% CI: 0.50, 0.72)


3 studies 2 studies 3 studies 4 studies

Spina bifida RR: 0.64 (95%CI: 0.57, 0.71)




Anencephaly RR: 0.76 (95%CI: 0.68, 0.85)




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Table 7 Summary of results for iron, folate and calcium/vitamin D fortification in women (Continued)

Serum folatelevels

SMD: 1.38 (95%CI: -0.20, 2.95)

No studies identified No studies identified SMD: 1.65 (95% CI: -0.51, 3.82) SMD: 0.45 (95% CI: -0.06, 0.97)


3 studies 2 studies

Iodine fortification

Outcome/quality of evidence Combined effect

Effect on hypothyroidism RR: 1.42 (95% CI: 1.11, 1.82)

Quality of evidence: Low 2 studies

Urinary iodine concentrations SMD: 7.16 (95% CI: 1.00, 13.31)

Quality of evidence: Moderate 4 studies

Calcium and vitamin D fortification

Outcome/quality of evidence Women of reproductive age Post-menopausal women

Vitamin D only Calcium and vitamin D Calcium only Vitamin D only

Serum parathyroid hormonelevels

SMD: 0.10 (95% CI: -0.28, 0.48) SMD: -0.23 (95% CI: -0.78, 0.32) No studies identified No studies identified

Quality of evidence: Low 2 studies 108 participants 1 study 52 participants

Serum vitamin D levels SMD: 0.26 (95% CI: -0.22, 0.75) SMD: -2.50 (95% CI: -3.22, -1.78) SMD: 0.69 (95% CI: 0.38, 1.00) No studies identified

Quality of evidence: Moderate 1 study 66 participants 1 study 55 participants 3 studies 228

Estimates in BOLD show significant impacts. CI, confidence intervals; NaFeEDTA: sodium iron ethylenediaminetetraacetate; RR: relative risk; SMD: standard mean difference.

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Table 8 Summary of results for multiple micronutrientfortification in women

Outcome/quality of evidence Combined effect

Hemoglobin levels SMD: 0.31 (95% CI: 0.13, 0.48)

Quality of evidence: Moderate 1 study 516 women

Serum ferritin levels SMD: 0.47 (95% CI: 0.36, 0.58)

Quality of evidence: Moderate 2 studies 1,214 women

Serum zinc levels SMD: 0.50 (95% CI: 0.38, 0.61)

Quality of evidence: Moderate 2 studies 1214 women

Serum retinol levels SMD: 0.47 (95% CI: 0.30, 0.65)


Effect on anemia RR: 0.76 (95% CI: 0.48, 1.21)


Estimates in bold show significant impacts. RR: relative risk; SMD: standardmean difference.


sulfate as the fortificant. Other forms of iron used wereferrous pyrophosphate, unspecified elemental iron andhydrogen-reduced iron. Twenty-two of the studies werecarried out in upper middle income countries (UMIC) andhigher income countries (HIC), and 18 were from lowermiddle income countries (LMIC) and lower income coun-tries (LIC). Eight of the studies were carried out in popula-tions with some form of iron deficiency or a comorbidity.A summary of results is presented in Table 3.Pooled analyses from the RCTs demonstrated a signifi-

cant increase in hemoglobin concentration (SMD: 0.55(95% CI: 0.34, 0.76)), serum ferritin levels (SMD: 0.91 (95%CI: 0.38, 1.44)) and reduction in anemia (RR: 0.55 (95% CI:0.42, 0.72)). A few studies reported the effect of iron fortifi-cation on cognition, but these could not be pooled togetherbecause the reported outcomes varied significantly.Subgroup analysis according to the various age groups

(infants, preschool and school going), countries (LIC/LMIC and UMIC/HIC) and baseline micronutrient status(deficient and normal populations) showed consistentfindings for all the outcomes assessed. The impacts onserum ferritin levels and anemia were significant for allthe three food vehicles, that is, processed food, condi-ments and staples, whereas the impact on hemoglobinlevels was significant for processed food and staples only.The effect of NaFeEDTA when used as the fortificant wassignificant on hemoglobin levels and anemia but was non-significant on serum ferritin levels. The impacts of ferroussulfate when used as the fortificant were significant for allthe three outcomes assessed.

ZincOur search strategy identified 10 studies examining zincfortification [34,41,44,53,59,78,91,100,103,125], seven oninfants, where infant formula feeds or milk were forti-fied, and three on school children, where porridge or

bread was fortified [53,59,91]. Eight of the studies wereRCTs and two were quasi-experimental designs. Thestudies varied in the duration of intervention rangingfrom 1 month to 12 months. Five studies employed zincsulfate as the fortificant; other compounds used werezinc oxide, zinc chloride and zinc acetate. A summary ofresults is presented in Table 4.Results from the RCTs showed a significant impact of

zinc fortification on increasing serum zinc concentration(SMD: 1.28 (95% CI: 0.56, 2.01)), whereas non-significantimpacts were observed for height velocity (SMD: 0.08 (95%CI: -0.53, 0.69)), weight gain (SMD: 0.50 (95% CI: -0.12,1.11)), serum alkaline phosphatase (SMD: 0.94 (95% CI: -0.29, 2.17)), hemoglobin levels (SMD: -0.11, (95% CI: -0.52to 0.31)) and serum copper levels (SMD: 0.22 (95% CI: -1.14 to 1.59)). Visual inspection of the forest plot forheight velocity showed that the study by Salmenperaet al. [98] was the main outlier; after sensitivity analysis,it showed significant improvements (SMD: 0.52 (95%CI: 0.01, 1.04)).Subgroup analysis showed a consistent positive effect on

serum zinc levels for both milk- and cereal-based prod-ucts, and for various durations of fortification (less thanand more than six months). For the various age groupsassessed, the effect was significant for only school-goingchildren with an asymptomatic deficiency at baseline. Theimpact on weight gain was non-significant across all thevarious age groups while the effect on height gain was sig-nificant only for infants with very low birth weight.

Vitamin D and calciumA total of seven RCTs, one quasi-experimental and twobefore-after studies were identified for vitamin D and cal-cium fortification [33,42,45,51,55,60,66,96,133,134]. Milkwas the preferred food vehicle and the amount of micro-nutrient used varied significantly among the studies. Onestudy was on preterm infants while the rest were on chil-dren and adolescents ranging from 6 years to 18 years ofage. A summary of results is presented in Table 5.Analysis of the results from RCTs showed that fortifi-

cation with vitamin D significantly increased serum con-centration of 25-hydroxy-vitamin D3 (SMD: 1.23 (95%CI: 0.35, 2.11)) and reduced serum parathyroid hormoneconcentration (SMD: -0.40 (95% CI: -0.56, -0.24)).

Vitamin AA total of three RCTs, one quasi-experimental and fourbefore-after studies were identified for vitamin A forti-fication [29,36,79,84,95,110,111,132]. The studies usedmonosodium glutamate, sugar and flour as the fortificant.These studies spanned from 6 months to 2 years in dur-ation. Five studies had children of ages ranging from 1 to6 years, and three studies had a range of 6 to 16 years ofage. A summary of results is presented in Table 5.


Analysis of the RCTs showed significant impacts onserum retinol concentration (SMD: 0.61 (95% CI: 0.39,0.83)) and hemoglobin levels (SMD: 0.48 (95% CI: 0.07,0.89)). A non-significant effect was shown on prevalenceof vitamin A deficiency (RR: 0.39 (95% CI: 0.09, 1.74)).

IodineIodine fortification was identified in seven studies[40,52,58,94,131,137,138]. All were before-after study de-signs evaluations of mass salt fortification programs.The analysis showed a significant effect on median

urinary iodine concentrations (SMD: 6.39 (95% CI: 2.69,10.08)) whereas the effect on serum thyroxin levels wasnon-significant (SMD: 0.45 (95% CI: -1.15, 2.06)). Asummary of results is presented in Table 5.

Dual fortificationTen studies were identified to study dual fortification[27,90,109,123,128,140-144]. Nine of the studies wereRCTs and one was a quasi-experimental design and in-cluded children ranging from 5 to 17 years. Iron and iodinewere the most commonly used micronutrients with salt asthe food vehicle. Our analysis showed a significant impactof iron and iodine fortification on hemoglobin concentra-tion (SMD: 0.53 (95% CI: 0.18, 0.89)) and on reducing theprevalence of anemia (RR: 0.47 (95% CI: 0.34, 0.66)).

Multiple micronutrientsMMN fortification was considered when three ormore micronutrients were fortified together. A total of 34studies were identified that reported outcomes on children[36,37,38,43,46,47,50,61-64,67-69,71-76,82,86,87,92,93,98,102,105,115,117,118,121,122,130]. Three of these werebefore-after studies and the rest were RCTs and quasi-experimental studies. Eleven studies had infants as theirstudy population, others included children up to 15 yearsof age. The duration of fortification ranged from 3 monthsto 4 years. All the studies employed targeted fortificationas their fortification strategy. A summary of results ispresented in Table 6.Analysis of the RCTs showed a significant effect of

MMN fortification on hemoglobin levels (SMD: 0.75(95% CI: 0.41, 1.08)), serum ferritin concentration (SMD:0.37 (95% CI: 0.13, 0.62)) and on reducing anemia preva-lence (RR: 0.55 (95% CI: 0.42, 0.71)). The impacts werenon-significant on serum zinc concentration, serum ret-inol concentration and vitamin A deficiency. MMN for-tification also had a non-significant impact on HAZ,WAZ and WHZ with a SMD of 0.13 (95% CI: -0.04,0.29), 0.11 (95% CI: -0.06, 0.28) and 0.04 (95% CI: -0.08,0.16) respectively, although showing positive trends.Analysis showed a non-significant effect on overall mor-bidity (including fever, UTI, diarrhea and respiratory in-fections) with a RR of 1.19 (95% CI: 0.98, 1.44). There

was a non-significant impact on diarrhea and respiratoryinfections but the incidence of UTIs was significantly re-duced, although the evidence of UTIs was from a singlestudy.Subgroup analyses for various age groups demon-

strated a significant impact on hemoglobin levels, serumferritin levels, anemia prevalence and HAZ in infants.Significant effects were observed in hemoglobin levels,serum ferritin levels and anemia prevalence for pre-school and school-going children. Subgroup analysesaccording to countries showed that MMN fortificationin LMIC/LIC and UMIC/HIC had significant impacts onhemoglobin levels, whereas in LIC/LMIC, the significantimpact was on serum ferritin levels and serum zinclevels.

WomenIron fortificationA total of 13 studies, including 11 RCTs, reported out-comes for the impact of iron fortification in women[35,151,154-156,173,175,178,203,204,216,218,223]. Vari-ous fortificants, including NaFeEDTA, ferrous sulfateand ferrous pyrophosphate, were used. Ten of the stud-ies were carried out in UMIC/HIC and three studieswere from LIC/LMIC. Four of the studies were carriedout in populations with some form of micronutrient de-ficiency or comorbidity. The most commonly reportedoutcomes included hemoglobin levels, serum ferritinlevels and anemia. A summary of results is presented inTable 7.Analysis of the RCTs showed a significant effect of

iron fortification on hemoglobin concentration (SMD:0.64 (95% CI: 0.30, 0.97)), serum ferritin levels (SMD:0.41 (95% CI: 0.23, 0.60)) and on prevalence of anemia(RR: 0.68 (95% CI: 0.49, 0.93)).Subgroup analyses showed that there was a significant

impact on hemoglobin and ferritin levels for both thehealthy and iron-deficient population, whereas the im-pact on anemia was only significant for iron-deficientpopulation. Further subgroup analyses based on coun-tries showed significant impacts of iron fortification onanemia and serum ferritin levels in LIC/LMIC andUMIC/HIC whereas hemoglobin was significantly af-fected only in UMIC/HIC. All different types offortificants used showed positive impact on anemiaprevalence and hemoglobin levels.

FolateThirty one before-after mass fortification studies wereidentified[149,150,153,157,159,164,168,169,172,174,177,181,184-186,189,193,195-197,199,200,202,205,206,209-211,221,222,224]. Flour was used as the food vehicle with thelevel of fortification varying from 40 μg/100 g to 500 μg/100 g. Duration of intervention varied between 1 and 10


years. A summary of results is presented in Table 7. Al-though anencephaly and spina bifida are two specific formsof neural tube defects, some studies described results forneural tube defects without mentioning the specific type.Thus we have pooled anencephaly, spina bifida and neuraltube defects separately as mentioned in studies to avoidany misinterpretation.Our analysis showed that folate fortification had a sig-

nificant impact in reducing neural tube defects (RR: 0.57(95% CI: 0.45, 0.73)), spina bifida (RR: 0.64 (95% CI:0.57, 0.71)) and anencephaly (RR: 0.80 (95% CI: 0.73,0.87)). The impacts were non-significant for red bloodcell folate levels (SMD: 1.26 (95% CI: -0.49, 3.01)), serumfolate concentration (SMD: 1.38 (95% CI: -0.20, 2.95))and twinning (RR: 1.06 (95% CI: 0.92, 1.22)).Subgroup analyses showed that use of various concen-

tration of folate (40 μg/100 g or more than 100 μg/100g) had consistent significant impacts in reducing neuraltube defects and spina bifida, whereas only 40 μg/100 gfolate fortification was effective in reducing incidence ofanencephaly. In a subgroup analysis based on durationof intervention of 1 year or more than 1 year, both hadsignificant impacts in reducing neural tube defects, spinabifida and anencephaly.

IodineA total of 16 studies were identified investigating iodinefortification [160-163,165-167,183,190,191,198,207,208,213,219,220]. All of these were before-after studies that usedmass fortification as the strategy with salt being the mostcommonly used food vehicle.The analysis showed that iodine fortification had a sig-

nificant impact on median urinary iodine concentrationswith a SMD of 7.16 (95% CI: 1.00, 13.31) and on the in-cidence of hypothyroidism with a RR of 1.42 (95% CI:1.11, 1.82). The effect was non-significant on serum thy-roxin levels with a SMD of 0.45 (95% CI: -1.15, 2.06).

Vitamin D and calciumA total of 13 RCTs and one before-after study were identi-fied for vitamin D and calcium fortification [146,147,158,170,171,179,180,182,187,192,194,201,212,215]. The level offortification varied significantly. Fortification durations var-ied from 2 weeks to 2 years. Reported outcomes includedserum parathyroid hormone levels, serum vitamin D levels,serum calcium levels and bone mineral density. Targetpopulations included WRA and post-menopausal women.A summary of results is presented in Table 7.The analysis showed that vitamin D and calcium fortifi-

cation in WRA had a non-significant impact on vitaminD3 levels with a SMD of −1.10 (95% CI: -3.81, 1.60) andserum parathyroid hormone levels with SMD of −0.01(95% CI: -0.32, 0.30). For the post-menopausal women,pooled analysis showed significant impacts on serum

concentration of 25-hydroxy-D3 with a SMD of 0.82 (95%CI: 0.30, 1.34) and on serum parathyroid hormone con-centration with SMD of −2.53 (95% CI: -4.42, -0.65).Results also indicated a significant impact of vitamin D

and calcium fortification on reducing the serum levels ofbone resorption markers: P1NP and CTx. Specifically,pooled analyses showed significantly reduced serum levelsof P1NP (three studies; SMD of −3.36 (95% CI: -6.37, -0.35)) and CTx (four studies; SMD of −4.93 (95% CI: -7.78,-2.08)) in both WRA and post-menopausal women

Multiple micronutrientsFive RCTs were identified for the impact of MMN forti-fication on women [148,176,188,214,217]. Varying num-ber (3 to 20) of micronutrients were used and theduration of intervention ranged from 6 months to 2years. The study population included WRA, pregnantand post-menopausal women. A summary of results ispresented in Table 8.Analysis showed that MMN fortification significantly

improved hemoglobin levels (SMD: 0.31 (95% CI: 0.13,0.48)), serum ferritin (SMD: 0.47 (95% CI: 0.36, 0.58)),serum zinc (SMD: 0.50 (95% CI: 0.38, 0.61)) and serumretinol (SMD: 0.47 (95% CI: 0.30, 0.65)), and reducedanemia prevalence (RR: 0.76 (95% CI: 0.48, 1.21)). How-ever, these findings should be interpreted with cautionas only a few studies were pooled for each outcome.

DiscussionVarious strategies have been pursued globally to alleviatenutritional deficiencies including food programs, dietmodification, supplementation and fortification. In this re-view, we have attempted to broadly quantify the impacts offortification of various commodities with micronutrients,singly or in combination, and to compare benefits.Our review of fortification strategies among children

does show significant impacts on increasing respectiveserum micronutrient concentrations, which could indir-ectly be used to assess impact at population level. Zincfortification led to a significant increase in serum zincconcentration, and the same was observed with vitamin Aand vitamin D fortification on respective serum micronu-trient concentrations. Fortification with iron or MMN for-tification was associated with a significant increase inserum ferritin, whereas the effect of MMN fortification onserum retinol and serum zinc was non-significant. Otherhematologic markers also improved following food fortifi-cation among children with vitamin A, iron and MMN,suggesting some conjoint benefits. Comparable to thefindings by others [65], the observed lack of negative ef-fects of zinc fortification on hemoglobin concentrationssuggests that that the quantities of zinc present in fortifiedfoods is not high enough to alter the absorption of iron.Although benefits of zinc fortification were seen on linear


growth, MMN fortification was not associated with anysignificant benefits on HAZ, WAZ and WHZ.Our analysis of the impact of fortification among

women indicates that calcium and vitamin D fortifica-tion do not lead to an increase in serum vitamin D3levels in WRA but has a significant effect in post-menopausal age groups. Iron fortification led to a signifi-cant increase in serum ferritin and hemoglobin levels inWRA and pregnant women. Folate fortification signifi-cantly reduced the incidence of congenital abnormalitieslike anencephaly, spinal bifida and neural tube defects.Similarly, fortification of salt with iodine decreased theincidence of hypothyroidism and led to higher medianurinary iodine concentrations. This evidence suggeststhat mass fortification strategies can be extremely pro-ductive and beneficial for numerous health outcomes.The total number of studies pooled for zinc and MMNfortification in women were insufficient to draw firmconclusions.Few studies in our review reported the direct impact

of fortification on morbidity. However, as many supple-mentation trials have already proven the effects of im-proved micronutrient status on morbidity, it could beinferred that these improvements in micronutrient sta-tus, reflected in changes in serum concentrations, couldalso have beneficial effects on health outcomes includingmorbidity and mortality. However, this cannot be defin-itely concluded without large scale studies measuringthe direct impact of fortification on such outcomes ordirect comparisons of fortification and supplementationstrategies.Notwithstanding the conclusions above, we are aware

that biochemical responses to specific micronutrient for-tification strategies may differ depending on the under-lying nutritional conditions of the individuals orpopulations, the micronutrient compound used for forti-fication, and the food vehicle chosen. To cater to thesevariations, which are inherent to this strategy, we under-took diverse subgroup analyses to confirm and accountfor the differences, where possible. For this, we dividedthe studies and reported separate estimates based on thevarious age groups targeted, baseline micronutrient sta-tus, compound and foods chosen, concentration of themicronutrient in the food, the duration of intervention,and whether the evidence was from HIC or LMIC. Ouranalyses suggest that the impact of food fortificationwere stronger in populations with nutritional deficien-cies at baseline, as there was greater hematological im-pact from food fortification with iron and MMNs inmarginalized at-risk populations. We also analyzed theimpact of food fortification on infants alone and the re-sults indicated that iron fortification was associated witha significant increase in serum ferritin and also a reduc-tion in the incidence of anemia, although effects on

hemoglobin concentrations were non-significant. Zincfortification in infants raised serum zinc concentrationswithout any observed benefits on linear growth andweight gain. MMN fortification significantly improvedhematological parameters and was also associated withsignificant gains in HAZ scores, whereas no beneficialeffects were observed for WAZ and WHZ.The choice of food and fortificant are critically import-

ant. The fortificant must be stable, have a long shelf lifeand should not alter the color, taste and appearance offood. The food matrix should not interfere with the ab-sorption of the micronutrient, thereby affecting its bio-availability, for example through phytates. Apart fromthe scientific aspects, the choice of food should be suchthat it is readily available to the target population andthe quantity consumed should be enough to match thedietary requirements. This is particularly true for chil-dren, who typically do not consume the same foods andstaples. A variety of food vehicles have been chosen forfortification, broadly classified as staples, condimentsand commercially processed foods. Our review showsthat, overall, staples have been the primary choice asthey are widely consumed by the population, whereasprocessed foods and cereals have been chosen when in-fants were the target population. Iodine fortification al-most exclusively used salt as a traditional and provenmethod, folate fortification was commonly employedthrough grains or grain products, and milk has been thecarrier of choice for vitamin D and calcium. Of the out-comes analyzed in this review, we could not concludewhether a specific compound was better for impactingindividual micronutrient status, as consistent resultswere observed for iron sulfate and NaFeEDTA whenused in iron fortification, and zinc sulfate, zinc chlorideand zinc oxide when used in zinc fortification. However,we did not compare costs or the cost effectiveness ofvarious approaches.The process of fortification comes with significant

costs, which have to be ultimately borne by the end con-sumer or the state. As the poor have limited purchasingpower, funding agencies and public private partnershipsare needed to provide costs subsidies and cost-sharingto ensure that the products reach those who need themmost. Additional demand creation and social marketingmay be necessary through campaigns to ensure adequatemarketing pull factors and consumption.Fortification promises to tackle a multitude of micro-

nutrient deficiencies through a single intervention: aone-window solution. Although the results are encour-aging, more is needed. The evidence from these sub-group analyses for different fortification vehicles andcompounds was not conclusive, and suggests that fur-ther trials are needed with defined functional and bio-logical outcomes. Most national programs analyzed were


from developed countries and data from the developingworld were relatively scarce. However, where available,the results showed comparable benefits. This scarcity ofstudies from developing countries is due to the fact thatnational fortification programs require large resources;robust scientific and research facilities are required toidentify the ideal food, micronutrient compound and in-dustrial support. The experience of commodities such aspre-fortified ready-to-use fortified foods indicates thatglobal procurement and supply as well as local produc-tion is possible.Our review has many limitations because we included

a range of studies of varying sizes and scientific rigor.This was due to the fact that large scale fortification pro-grams are, in general, before-after evaluations. Manystudies used different foods and concentrations ofmicronutrients and the frequency of feeding/intake wasnot uniform. Limited information on confounding fac-tors like age and nutritional status at the initiation of theintervention also limited inference of outcomes by agebands and nutrition categories, and the duration of theintervention period evaluated also varied across studies.There is limited evidence available for the direct impactof fortification on anthropometric measures, morbidityand mortality and these are essential to evaluate futurebenefits and effective strategies. We propose that furtherfuture trials are warranted, which should take into con-sideration the limitations identified in this review anddraw upon this, so that we have a pool of appropriatestudies with good quality study designs to impute the ac-tual impacts of this promising strategy.

ConclusionFortification, though promising, is not an answer to theglobal widespread nutritional deficiencies. With highburdens of diarrhea and enteropathy, widespread malab-sorption may be a barrier to this strategy taking maximaleffect. Integration of fortification and supplementationstrategies together with other mother and child healthand prevention programs may be the answer to addressthe widespread global under-nutrition and to ensure sus-tainable benefits. Community education and promotioncampaigns should also be implemented parallel to theprimary fortification programs to increase awareness, ac-ceptability and equity. Fortification is potentially an ef-fective strategy but evidence from the developing worldis scarce and future programs also need to assess the di-rect impact of fortification on morbidity and mortality.

Additional files

Additional file 1: Characteristics of included studies.

Additional file 2: Forest plots.

Additional file 3: Summary of findings and quality of outcomes.

AbbreviationsCI: Confidence interval; GRADE: Grading of Recommendations Assessment,Development and Evaluation; HAZ: Height for age Z-scores; HIC: High-income countries; LIC: Lower-income countries; LMIC: Lower middle-incomecountries; MMN: Multiple micronutrient; OR: Odds ratio; RCT: Randomizedcontrolled trial; RR: Relative risk; SMD: Standard mean difference;UMIC: Upper middle-income countries; UTI: Urinary tract infections;WAZ: Weight for age Z-scores; WHZ: Weight for height Z-scores; WHO:World Health Organization; WRA: Women of reproductive age.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsZAB was responsible for designing and coordinating the review. JKD, RASand RK were responsible for data collection, screening the search results,screening retrieved papers against inclusion criteria, appraising quality ofpapers, abstracting data from papers, entering data into RevMan, analysisand interpretation of data and writing the review. ZAB and JKD criticallyreviewed and modified the manuscript. All authors read and approved thefinal manuscript.

AcknowledgmentsWe would like to acknowledge Sohni Dean and Zohaib Sohail, who helpedus in the search and abstraction of data for the iron and iodine fortificationcomponents respectively. We would also like to thanks our ResearchAssistant Talha Mirza for his administrative support. We are grateful to theNestle Nutrition Institute for its unrestricted support towards the genesis ofthis review and its external assessment in an advisory group meeting inZurich in October 2011.

Received: 16 January 2013 Accepted: 5 August 2013Published: 23 August 2013

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RESEARCH Open Access Micronutrient fortification of food and … · 2012. 11. 1. · approach is...

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